Leucocytosis
Conditions
Keywords
neutrophil count, filgrastim, granulocyte colony-stimulating factor
Brief summary
BCD-002-1 is 1 phase clinical trial to evaluate pharmacokinetics, pharmacodynamics and safety of single-injection of Leucostim® to healthy volunteers compared to Neupogen®
Interventions
BIOLOGICALLeucostim®
Leucostim® is filgrastim biosimilar.
BIOLOGICALNeupogen®
Sponsors
Biocad
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Written informed consent. * Male gender. * Age between 18 and 45 years. * Normal body mass index. * Verified diagnosis healthy, established according to the anamnesis, physical examination and laboratory findings. * Absence of alcohol or drug abuse.
Exclusion criteria
* History of use of filgrastim. * Allergy to any components of study drugs. * Acute hemorrhage, donation of blood / plasma or blood transfusions during last 2 months prior to enrollment in the study, history of chronic bleeding. * Surgical interventions during last 30 days prior to screening or planed surgical intervention during the study. * Any diseases that could interfere with pharmacokinetics of filgrastim, including chronic liver, liver or blood diseases, diseases of cardiovascular, lung and neuroendocrine systems. * Fever with body temperature higher than 40°С.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC (0-48 Hours) | 0 to 48 hours post-dose | Area Under Curve (AUC) concentration - time from the moment of filgrastim injection to 48 hours |
| Cmax After Subcutaneous Injection | 0 to 48 hours post-dose | Maximal concentration of filgrastim after subcutaneous injection of filgrastim |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Т½ | 0 to 48 hours post-dose | Half-life of filgrastim after single injection of filgrastim |
| Kel | 0 to 48 hours post-dose | The elimination rate constant after single injection of filgrastim |
| Clearance | 0 to 48 hours post-dose | Clearance of filgrastim after single injection |
| ANC-AUEC (0-336 Hours) | 0 to 336 hours post-dose | Area Under Effect Curve (AUEC) effect - time from the moment of filgrastim injection to 336 hours based on absolute neutrophil count (ANC) |
| ANC-Emax | 0 to 336 hours post-dose | Maximal absolute neutrophil count after single filgrastim injection |
| CD34-AUEC (0-336 Hours) | 0 to 336 hours post-dose | Area Under Effect Curve (AUEC) effect - time from the moment of filgrastim injection to 336 hours based on CD-34 cells count (CD34) |
| Cmax After Intravenous Injection | 0 to 48 hours post-dose | Maximal concentration of filgrastim after intravenous injection of filgrastim |
| Overall Frequency of Serious Adverse Events (SAE) | 0 to 336 hours post-dose | — |
| Overall Frequency of Adverse Events (AE) | 0 to 336 hours post-dose | — |
| Frequency of Local Reactions | 0 to 336 hours post-dose | — |
| Frequency of AE/SAE 3-4 Grade CTCAE 4.03 | 0 to 336 hours post-dose | Grading scale of CTCAE 4.03 Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL (activities of daily living). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. |
| Frequency of Preliminary Withdrawal Due to AE/SAE | 0 to 336 hours post-dose | — |
| Proportion of Patients With Binding or Neutralizing Antibodies to Filgrastim | 0 to 336 hours post-dose | Proportion of patients who had developed binding or neutralizing antibodies to filgrastim after single injection. |
| CD34-Emax | 0 to 336 hours post-dose | Maximal absolute count of CD34-cells after single filgrastim injection |
| Tmax After Injection | 0 to 48 hours post-dose | Time after single injection to reach maximal concentration of filgrastim |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Leucostim® --> Neupogen®, Subcutaneous Injections Healthy volunteers in this group received single subcutaneous injection Leucostim® on Day 1 followed by single subcutaneous injection Leucostim® on Day 29.
Leucostim®: Leucostim® is filgrastim biosimilar.
Neupogen® | 18 |
| Neupogen® --> Leucostim®, Subcutaneous Injections Healthy volunteers in this group received single subcutaneous injection Neupogen®, on Day 1 followed by single subcutaneous injection Leucostim® on Day 29.
Leucostim®: Leucostim® is filgrastim biosimilar.
Neupogen® | 18 |
| Leucostim® --> Neupogen®, Intravenous Injections Healthy volunteers in this group received single intravenous injection Leucostim® on Day 1 followed by single intravenous injection Leucostim® on Day 29.
Leucostim®: Leucostim® is filgrastim biosimilar.
Neupogen® | 12 |
| Neupogen® --> Leucostim®, Intravenous Injections Healthy volunteers in this group received single intravenous injection Neupogen® on Day 1 followed by single subcutaneous intravenous Leucostim® on Day 29.
Leucostim®: Leucostim® is filgrastim biosimilar.
Neupogen® | 12 |
| Total | 60 |
Baseline characteristics
| Characteristic | Leucostim® --> Neupogen®, Subcutaneous Injections | Neupogen® --> Leucostim®, Subcutaneous Injections | Leucostim® --> Neupogen®, Intravenous Injections | Neupogen® --> Leucostim®, Intravenous Injections | Total |
|---|---|---|---|---|---|
| Age, Continuous | 22.94 years | 25.41 years | 23.48 years | 27.30 years | 24.63 years |
| Race and Ethnicity Not Collected | — | — | — | — | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 18 Participants | 18 Participants | 12 Participants | 12 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 36 | 0 / 24 | 0 / 23 |
| other Total, other adverse events | 36 / 36 | 35 / 36 | 22 / 24 | 22 / 23 |
| serious Total, serious adverse events | 0 / 36 | 0 / 36 | 0 / 24 | 0 / 23 |
Outcome results
Primary
AUC (0-48 Hours)
Area Under Curve (AUC) concentration - time from the moment of filgrastim injection to 48 hours
Time frame: 0 to 48 hours post-dose
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Leucostim® Subcutaneous Injections | AUC (0-48 Hours) | 168603.588 picogram per ml / hour | Standard Deviation 47721.48 |
| Neupogen® Subcutaneous Injections | AUC (0-48 Hours) | 181152 picogram per ml / hour | Standard Deviation 54706.439 |
| Leucostim® Intravenous Injections | AUC (0-48 Hours) | 411826.811 picogram per ml / hour | Standard Deviation 204285.095 |
| Neupogen® Intravenous Injections | AUC (0-48 Hours) | 427355.99 picogram per ml / hour | Standard Deviation 170878.6 |
Primary
Cmax After Subcutaneous Injection
Maximal concentration of filgrastim after subcutaneous injection of filgrastim
Time frame: 0 to 48 hours post-dose
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Leucostim® Subcutaneous Injections | Cmax After Subcutaneous Injection | 21605.163 picogram per ml | Standard Deviation 5247.467 |
| Neupogen® Subcutaneous Injections | Cmax After Subcutaneous Injection | 23389.559 picogram per ml | Standard Deviation 7549.536 |
Secondary
ANC-AUEC (0-336 Hours)
Area Under Effect Curve (AUEC) effect - time from the moment of filgrastim injection to 336 hours based on absolute neutrophil count (ANC)
Time frame: 0 to 336 hours post-dose
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Leucostim® Subcutaneous Injections | ANC-AUEC (0-336 Hours) | 1924.284 cells х10^9 per liter/hour | Standard Deviation 326.455 |
| Neupogen® Subcutaneous Injections | ANC-AUEC (0-336 Hours) | 1933.358 cells х10^9 per liter/hour | Standard Deviation 309.533 |
| Leucostim® Intravenous Injections | ANC-AUEC (0-336 Hours) | 1860.922 cells х10^9 per liter/hour | Standard Deviation 372.861 |
| Neupogen® Intravenous Injections | ANC-AUEC (0-336 Hours) | 1895.82 cells х10^9 per liter/hour | Standard Deviation 426.826 |
Secondary
ANC-Emax
Maximal absolute neutrophil count after single filgrastim injection
Time frame: 0 to 336 hours post-dose
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Leucostim® Subcutaneous Injections | ANC-Emax | 21.285 cells х10^9 per liter | Standard Deviation 4.593 |
| Neupogen® Subcutaneous Injections | ANC-Emax | 20.803 cells х10^9 per liter | Standard Deviation 4.097 |
| Leucostim® Intravenous Injections | ANC-Emax | 20.726 cells х10^9 per liter | Standard Deviation 6.393 |
| Neupogen® Intravenous Injections | ANC-Emax | 21.602 cells х10^9 per liter | Standard Deviation 5.93 |
Secondary
CD34-AUEC (0-336 Hours)
Area Under Effect Curve (AUEC) effect - time from the moment of filgrastim injection to 336 hours based on CD-34 cells count (CD34)
Time frame: 0 to 336 hours post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Leucostim® Subcutaneous Injections | CD34-AUEC (0-336 Hours) | 1289 cell per microliter / hour | Standard Deviation 762.292 |
| Neupogen® Subcutaneous Injections | CD34-AUEC (0-336 Hours) | 1200.667 cell per microliter / hour | Standard Deviation 761.29 |
| Leucostim® Intravenous Injections | CD34-AUEC (0-336 Hours) | 1350.783 cell per microliter / hour | Standard Deviation 716.645 |
| Neupogen® Intravenous Injections | CD34-AUEC (0-336 Hours) | 1251.652 cell per microliter / hour | Standard Deviation 562.087 |
Secondary
CD34-Emax
Maximal absolute count of CD34-cells after single filgrastim injection
Time frame: 0 to 336 hours post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Leucostim® Subcutaneous Injections | CD34-Emax | 7.694 cell per microliter | Standard Deviation 4.839 |
| Neupogen® Subcutaneous Injections | CD34-Emax | 7.056 cell per microliter | Standard Deviation 5.248 |
| Leucostim® Intravenous Injections | CD34-Emax | 9 cell per microliter | Standard Deviation 6.267 |
| Neupogen® Intravenous Injections | CD34-Emax | 7.522 cell per microliter | Standard Deviation 4.22 |
Secondary
Clearance
Clearance of filgrastim after single injection
Time frame: 0 to 48 hours post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Leucostim® Subcutaneous Injections | Clearance | 2048.087 ml per hour |
| Neupogen® Subcutaneous Injections | Clearance | 1981.707 ml per hour |
| Leucostim® Intravenous Injections | Clearance | 965.938 ml per hour |
| Neupogen® Intravenous Injections | Clearance | 830.442 ml per hour |
Secondary
Cmax After Intravenous Injection
Maximal concentration of filgrastim after intravenous injection of filgrastim
Time frame: 0 to 48 hours post-dose
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Leucostim® Subcutaneous Injections | Cmax After Intravenous Injection | 79751.577 picogram per ml | Standard Deviation 24810.907 |
| Neupogen® Subcutaneous Injections | Cmax After Intravenous Injection | 90796.227 picogram per ml | Standard Deviation 25925.283 |
Secondary
Frequency of AE/SAE 3-4 Grade CTCAE 4.03
Grading scale of CTCAE 4.03 Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL (activities of daily living). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.
Time frame: 0 to 336 hours post-dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Leucostim® Subcutaneous Injections | Frequency of AE/SAE 3-4 Grade CTCAE 4.03 | 0 Participants |
| Neupogen® Subcutaneous Injections | Frequency of AE/SAE 3-4 Grade CTCAE 4.03 | 1 Participants |
| Leucostim® Intravenous Injections | Frequency of AE/SAE 3-4 Grade CTCAE 4.03 | 0 Participants |
| Neupogen® Intravenous Injections | Frequency of AE/SAE 3-4 Grade CTCAE 4.03 | 0 Participants |
Secondary
Frequency of Local Reactions
Time frame: 0 to 336 hours post-dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Leucostim® Subcutaneous Injections | Frequency of Local Reactions | 0 Participants |
| Neupogen® Subcutaneous Injections | Frequency of Local Reactions | 0 Participants |
| Leucostim® Intravenous Injections | Frequency of Local Reactions | 0 Participants |
| Neupogen® Intravenous Injections | Frequency of Local Reactions | 0 Participants |
Secondary
Frequency of Preliminary Withdrawal Due to AE/SAE
Time frame: 0 to 336 hours post-dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Leucostim® Subcutaneous Injections | Frequency of Preliminary Withdrawal Due to AE/SAE | 0 Participants |
| Neupogen® Subcutaneous Injections | Frequency of Preliminary Withdrawal Due to AE/SAE | 0 Participants |
| Leucostim® Intravenous Injections | Frequency of Preliminary Withdrawal Due to AE/SAE | 0 Participants |
| Neupogen® Intravenous Injections | Frequency of Preliminary Withdrawal Due to AE/SAE | 0 Participants |
Secondary
Kel
The elimination rate constant after single injection of filgrastim
Time frame: 0 to 48 hours post-dose
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Leucostim® Subcutaneous Injections | Kel | 0.158 hour-1 |
| Neupogen® Subcutaneous Injections | Kel | 0.161 hour-1 |
| Leucostim® Intravenous Injections | Kel | 0.252 hour-1 |
| Neupogen® Intravenous Injections | Kel | 0.272 hour-1 |
Secondary
Overall Frequency of Adverse Events (AE)
Time frame: 0 to 336 hours post-dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Leucostim® Subcutaneous Injections | Overall Frequency of Adverse Events (AE) | 36 Participants |
| Neupogen® Subcutaneous Injections | Overall Frequency of Adverse Events (AE) | 35 Participants |
| Leucostim® Intravenous Injections | Overall Frequency of Adverse Events (AE) | 22 Participants |
| Neupogen® Intravenous Injections | Overall Frequency of Adverse Events (AE) | 22 Participants |
Secondary
Overall Frequency of Serious Adverse Events (SAE)
Time frame: 0 to 336 hours post-dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Leucostim® Subcutaneous Injections | Overall Frequency of Serious Adverse Events (SAE) | 0 Participants |
| Neupogen® Subcutaneous Injections | Overall Frequency of Serious Adverse Events (SAE) | 0 Participants |
| Leucostim® Intravenous Injections | Overall Frequency of Serious Adverse Events (SAE) | 0 Participants |
| Neupogen® Intravenous Injections | Overall Frequency of Serious Adverse Events (SAE) | 0 Participants |
Secondary
Proportion of Patients With Binding or Neutralizing Antibodies to Filgrastim
Proportion of patients who had developed binding or neutralizing antibodies to filgrastim after single injection.
Time frame: 0 to 336 hours post-dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Leucostim® Subcutaneous Injections | Proportion of Patients With Binding or Neutralizing Antibodies to Filgrastim | 0 Participants |
| Neupogen® Subcutaneous Injections | Proportion of Patients With Binding or Neutralizing Antibodies to Filgrastim | 0 Participants |
| Leucostim® Intravenous Injections | Proportion of Patients With Binding or Neutralizing Antibodies to Filgrastim | 0 Participants |
| Neupogen® Intravenous Injections | Proportion of Patients With Binding or Neutralizing Antibodies to Filgrastim | 0 Participants |
Secondary
Tmax After Injection
Time after single injection to reach maximal concentration of filgrastim
Time frame: 0 to 48 hours post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Leucostim® Subcutaneous Injections | Tmax After Injection | 4 hours |
| Neupogen® Subcutaneous Injections | Tmax After Injection | 4 hours |
| Leucostim® Intravenous Injections | Tmax After Injection | 0.5 hours |
| Neupogen® Intravenous Injections | Tmax After Injection | 0.5 hours |
Secondary
Т½
Half-life of filgrastim after single injection of filgrastim
Time frame: 0 to 48 hours post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Leucostim® Subcutaneous Injections | Т½ | 4,386 hours |
| Neupogen® Subcutaneous Injections | Т½ | 4,307 hours |
| Leucostim® Intravenous Injections | Т½ | 2,746 hours |
| Neupogen® Intravenous Injections | Т½ | 2,549 hours |